Blood gas analyses are performed in most hospital laboratories for the purpose of diagnosing and treating abnormalities of pulmonary function and acid/base balances. The three parameters measured are blood pH, CO.sub.2 partial pressure (P.sub.CO.sbsb.2), and oxygen partial pressure (P.sub.O.sbsb.2). Additionally, hemoglobin tests may also be performed. These tests include the determination of total deoxyhemoglobin, oxyhemoglobin, carboxyhemoglobin and methemoglobin.
In performing the pH, P.sub.O.sbsb.2 and P.sub.CO.sbsb.2, tests a blood sample is drawn from the patient and introduced into specialized equipment containing electrodes which are specific for the parameter to be measured. Since blood deteriorates rapidly and dissolved gases tend to come out of solution, it must be analyzed promptly, or within a few hours if the blood has been cooled on ice.
It is, of course, axiomatic that the test results can be no better than the instrumentation used. Therefore, it is necessary to monitor the equipment for proper calibration and function. While an extraneous gas source can be used to standardize blood gas control equipment, the electrodes used in testing are sensitive to the test medium. For example when oxygen in the gaseous state is used as the standard, an instrument reading is obtained which is different from that obtained when the standard is a liquid containing dissolved oxygen. This liquid-gas difference is a result of differences in rates of diffusion of oxygen through the gaseous or liquid medium with which it is associated.
In order to alleviate the need for mathematical corrections to compensate for this liquid-gas difference, it has been recognized that a liquid control is preferred to a gaseous control. The preferred liquid would, of course, be blood since it comprises all of the constituents to which the test instrument is exposed. Blood, however, deteriorates rapidly and loses dissolved gases. In addition, as a result of cellular metabolism, P.sub.CO.sbsb.2 increases while P.sub.O.sbsb.2 and pH decrease. Since there is no recognized process for preventing these changes from occurring in stored whole blood, it has been rejected as a control.
The first liquid blood gas controls were buffered water solutions containing dissolved gases. While these solutions avoided the liquid-gas difference problem, they lacked other components of blood which effect the sensitive electrode components of the test equipment.
As a first step in resolving that problem, controls were prepared which contained soluble hemoglobin. These controls, however, lacked the methemoglobin reductase enzyme which, in the blood cell, reduces iron to the Fe.sup.++ state. As a consequence the iron of the hemoglobin is always in the Fe.sup.+++ state, that is, the hemoglobin is themoglobin. Hence, these controls can only be used for total hemoglobin analyses. More recently, controls have been developed which more closely approximate whole blood.
U.S. Pat. No. 3,859,049 teaches a method for stabilizing whole blood and whole blood components utilizing fluorides, citrates, fluoroacetic acid and iodoacetic acid. Typically, sodium fluoride, sodium citrate, and fluoroacetic or iodoacetic acid are added to whole blood. The mixture is refrigerated and allowed to age for a period sufficient to stabilize P.sub.CO.sbsb.2, P.sub.O.sbsb.2 and pH levels. Unfortunately, the product has a short shelf life of about one month. A product with a longer shelf life has been prepared by treating the blood components with an aldehyde.
U.S. Pat. No. 3,973,913 teaches a method for stabilizing red blood cells by separating them from whole blood and stabilizing them by treatment with an aldehyde, e.g., formaldehyde or glutaraldehyde. These stabilized cells are added to a buffered solution containing glucose, neomycin and chloramphenicol as bactericides, and salt to provide an isotonic solution which has an osmolality similar to that of blood. This product has a shelf life of only two months, however, and the cells rapidly lose hemoglobin which is oxidized to methemoglobin.
What is needed is an improved stabilizing technique which will result in more stable blood gas and hemoglobin analysis controls which simulate whole blood.
As used in the specification and claims, the term "hemoglobin analysis" means those hemoglobin tests which measure total hemoglobin, percent oxyhemoglobin, percent carboxyhemoglobin and percent methemoglobin. Other parameters such as volume % O.sub.2 and CO.sub.2 can be calculated from the observed values.
Dimethyl adipimidate has been disclosed as a cross linking agent for erythrocyte membranes; see Niehaus, W.G., et al. "Cross-Linking of Erythrocyte Membranes With Dimethyl Adipimidate," Biochem. Biophys. Acta 196: 170-175 (1970).
In other studies dimethyl adipimidate (DMA) has been disclosed as being an antisickling agent for red blood cells; see "Dimethyl Adipimidate: A New Antisickling Agent," Lubin, B.H., et al., Proc. Nat. Acad. Sci. U.S.A., Vol. 72, No. 1 pp 43-46, Jan. 1975 and "Antisickling Nature of Dimethyl Adipimidate," Waterman, M. R. et al, Biochem Biophys. Res. Comm., Vol. 63: No. 3, 580-587 (1975).
More recently the cross-linking effects of DMA have been shown to inhibit enzyme activity; see "The Effect of Crosslinking Reagents on Red-Cell Shape," Mentzer, W. C. and Lubin, B. H., Seminars in Hematology 16:115-127 (April 1979). Additionally, DMA has been shown to affect ion retention in erythrocytes. Krinsky, N. I., et al. "Retention of K.sup.+ Gradients in Imidoester Crosslinked Erythrocyte Membranes," Arch. Biochem. Biophys., 160, 350-352 (1974).
No application of DMA cross-linking of erythrocyte membranes to blood gas controls is disclosed in the prior art.